CNS disorders are a type of neurological disorder. CNS disorders can be drug induced, can be attributed to genetic predisposition, infection or trauma, or can be of unknown etiology, CNS disorders comprise neuropsychiatric disorders, neurological diseases and mental illnesses, and include neurodegenerative diseases, behavioral disorders, cognitive disorders and cognitive affective disorders. There are several CNS disorders whose clinical manifestations have been attributed to CNS dysfunction (i.e., disorders resulting from inappropriate levels of neurotransmitter release, inappropriate properties of neurotransmitter receptors, and/or inappropriate interaction between neurotransmitters and neurotransmitter receptors). Several CNS disorders can be attributed to a cholinergic deficiency, a dopaminergic deficiency, an adrenergic deficiency and/or a serotonergic deficiency. CNS disorders of relatively common occurrence include presenile dementia (early onset Alzheimer's disease), senile dementia (dementia of the Alzheimer's type), Parkinsonism including Parkinson's disease, Huntington's chorea, tardive dyskinesia, hyperkinesia, mania, attention deficit disorder, anxiety, dyslexia, schizophrenia and Tourette's syndrome.
Parkinson's disease (PD) is a debilitating neurodegenerative disease, presently of unknown etiology, characterized by tremors and muscular rigidity. A feature of the disease appears to involve the degenerative of dopaminergic neurons (i.e., which secrete dopamine). One symptom of the disease has been observed to be a concomitant loss of nicotinic receptors which are associated with such dopaminergic neurons, and which are believed to modulate the process of dopamine secretion. See, Rinne, et al., Brain Res., Vol. 54, pp. 167-170 (1991) and Clark, et al., Br. J, Pharm., Vol. 85, pp. 827-835 (1985). It also has been proposed that nicotine can ameliorate the symptoms of PD. See, Smith et al., Rev. Neurosci., Vol. 3(1), pp. 25-43 (1982).
The combination of levodopa and carbidopa in considered to be the most effective treatment for symptoms of Parkinson's disease (The Medical Letter, 35:31-34), 1993). For subjects afflicted with and/or diagnosed with Parkinson's disease, the benchmark treatment is typically oral administration of a dosage form containing levodopa in combination with carbidopa. Levodopa is a precursor of dopamine but unlike dopamine, is able to cross the blood brain barrier. However, while in the peripheral blood system and prior to crossing the blood brain barrier, levodopa is decarboxylated into dopamine. Carbidopa inhibits the rapid peripheral decarboxylation of levodopa into dopamine. The negates the need for high doses of levodopa which would result in adverse events, i.e., side effects, in particular nausea, caused by the dopamine released into the circulation from levodopa conversion in the intestinal mucosa and other peripheral tissues. Currently, oral levodopa/carbidopa combination drug products on the market consist of immediate release tables, for example, Sinemet® and Atamet®, and extended release tables, for example, Sinemet® CR and generics. Carbidopa is also available as single-ingredient tablets for those patients who require additional carbidopa when taking the combination tablets.
Immediate release levodopa/carbidopa tablets are administered three or four times a day and the extended release product is administered two to three times a day. Recently, an external pump that infuses levodopa and carbidopa into the duodenum at a controlled rate through a surgical opening in the stomach became available in Europe and Canada (Duodopa®, Solvay Pharmaceuticals, Germany).
It is know that exposure of affected neurons in Parkinson's disease to exogenous dopamine in a pulsatile fashion, such as in oral administration of levodopa in immediate release form to Parkinson's patients, eventually, in two to three years, leads to the development of the “on-off” phenomenon, i.e., mobility is improved for a couple of hours after each dose, but rigidity and akinesia return at the end of the dosing interval. Dosing more frequently would improve this but dyskinesia, excessive and abnormal involuntary movement, would occur when levodopa level becomes high. It is also know that when levodopa levels are maintained constant by IV infusion at a constant rate, the on-off phenomena and dyskinesia are reduced. This is also mimicked by taking subdivided daily oral doses frequently, such as every two hours instead of four or six hours. The later can in theory be realized in an oral extended release dosage forms. However, the unique oral absorption characteristics of levodopa have present problems in achieving an oral extended/controlled release dosage form that delivers the drug at a relatively constant rate for an extended period of time to achieve relatively constant plasma levels of levodopa.
As levodopa is only absorbed in the proximal small intestine via an active transport mechanism for aromatic amino acids, this limits the performance of conventional oral controlled release dosage forms which are rapidly emptied from the stomach into the intestine. If the duration of release is long compared to the transit time through the small intestine, about 2 to 3 hours, most of the drug is not delivered to the site of absorption in the proximal small intestine and is not absorbed. Hence, the duration of release in the small intestine has to be relatively short in order not to lose bioavailability.
Such is the case for SINEMET® CR, for which complete in vitro release (dissolution apparatus 1, paddle, pH 1) occurs in about 2.5 hours. Formulations with longer release durations resulted in lower bioavailability of levodopa. Even so, SINEMET® CR bioavailability is only 70-75% of the immediate release tablet SINEMET®. Administration with food increases the bioavailability substantially since gastric emptying is slowed. Despite FDA recommended dosing of the drug two to three times a day, in actual clinical practice, some patients may require administration of the drug four to six times a day due.
A duodenum infusion pump can deliver levodopa and carbidopa, at a constant rate, directly to the intestinal site of absorption thereby mitigating the above problems. But such therapy is neither convenient in initiation (surgical insertion of infusion tubing) nor in maintenance (wound and device care).
Thus, there is a strong need in the art for pharmaceutical compositions that effectively and conveniently aide in the treatment and prevention of movement disorders, such as Parkinson's Disease, by providing extended/controlled release of levodopa and carbidopa at a relatively constant rate for an extended period of time to achieve relatively constant plasma levels. The present disclosure meets these needs, among others.
Additional embodiments of the present method, compositions, and the like will be apparent from the following description, drawings, examples, and claims. As can be appreciated from the foregoing and following description, each and every feature described herein, and each and every combination of two or more of such features, is included within the scope of the present disclosure provided that the features included in such a combination are not mutually inconsistent. In addition, any feature or combination of features may be specifically excluded from any embodiment of the present invention. Additional aspects and advantages of the present invention are set forth in the following description and claims, particularly when considered in conjunction with the accompanying examples and drawings.